There are approximately 100,000 individuals living with sickle cell disease in the US, however study after study has shown that many lack access to the few existing evidence based interventions such as hydroxyurea. We need to investigate novel ways to increase acess to hematology care and disease modifying therapies.

Hydroxyurea is a widely available disease-modifying therapy for sickle cell disease (SCD), but its effectiveness is currently limited by inadequate utilization, and less than optimal response. Research is needed to improve adherence to this evidence-based therapy and emphasis needs to be placed on determining whether therapy with hydroxyurea can prevent or even reverse organ dysfunction. In addition, research identifying new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease, and pulmonary hypertension will be valuable in the management and treatment of SCD.

Name of idea submitter and other team members who worked on this idea:
Alice Kuaban on behalf of the American Society of Hematology (ASH)

Voting

• There is a need to develop and support formal programs to provide follow-up care for newborns who test positive for the sickle cell trait or sickle cell disease upon screening. While newborn screening programs exist nationwide, healthcare providers report that often, screening is conducted only upon request (likely related to cost) and there is usually no follow-up afterwards. Interventions are also needed further
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We and others have demonstrated that a doctor diagnosis of asthma is associated with increased morbidity and mortality in those with SCD. While doctor diagnosis of asthma is the issue for children, wheezing symptoms even without a diagnosis is the risk factor for adults.

This suggests either that asthma is under diagnosed in adults or that the disease patterns shifts from childhood to adulthood.

Making a diagnosis of asthma in individuals with SCD is difficult, as SCD by itself causes respiratory symptoms that can be similar to asthma in general populations, but diagnostic criteria are being proposed. There is concern about the value of treatment of the co-morbid of asthma in prevention of symptoms and even more so in reducing morbidity of pain and ACS episodes. There is also concern with regard to the potential side effects of inhaled corticosteroids by themselves increasing pain episodes and also having adverse effects on bone density, which can be affected by SCD itself.

Name of idea submitter and other team members who worked on this idea:
ATS Member

It has been reported for many decades that the sickle cell trait population are an asymptomatic group; however, there have been an increasing number of reports in the media and the medical literature suggesting the opposite.

Name of idea submitter and other team members who worked on this idea:
Sickle Cell Warriors, Inc. community members

Voting

From various publications and reports, we have characterized the risks associated with sickle cell disease (SCD) and understand many of the barriers for treatment of SCD in LMICs. How can implementation science research be used to reduce the negative outcomes of SCD in low/middle income countries?

Millions of people in the U.S and throughout the world have sickle cell trait, yet other than its impact on athletes and the recent finding that it may significantly raise the risk of chronic kidney disease, little is known about the trait’s effect on the health of those who carry it. Additional research is needed to further elucidate the implications of sickle cell trait alone, in combination with other genetic tendencies or in response to certain environmental factors. Findings can be used to provide evidence-based clinical guidance for the millions of people who may be affected

Feasibility and challenges of addressing this CQ or CC:

Addressing this question is feasible. Obtaining sufficient long-term data to answer these questions may be challenging.

Name of idea submitter and other team members who worked on this idea:
The Sickle Cell Association of New Jersey

Voting

Challenges that need to be overcome in blood transfusion, especially in SCD, include:
a. Adopting molecular genotyping as the standard in blood transfusion therapy.
b. Advancing new generation, anti-oxidant hemoglobin-based oxygen carriers (HBOCs) for use in emergencies such as trauma, stroke, acute hemolysis, and in transfusion in SCD and related disorders. In SCD, HBOCs have the capacity to not only serve as substitutes
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Transfusion of RBC is major adjunct in the management of trauma, acute and chronic illness. Issues in blood transfusion include availability of donors, RBC typing and crossmatching, cold storage of donor cells, and limited viability of stored RBC. Globally, in many situations where blood is critically needed, these systems are not available.

An increasing percentage of people with SCD require regular RBC transfusion to prevent stroke and other major complications. In addition, RBC transfusion is employed repeatedly in the management of serious acute complications of SCD. Transfusion of normal RBC to replace or supplement the patient’s defective RBC is the most effective intervention in the management of SCD.

Impacts:

• Molecular genotyping of RBC will reduce alloimmunization.

• Use of new generation HBOCs that do not require blood typing, crossmatching, refrigeration, and that do not transmit infection, would save lives in conditions of severe hemorrhage, stroke, possibly heart attack, especially where there is no immediate access to adequate medical facilities.

• In SCD, HBOCs could prevent pain or reduce its severity and duration, prevent stroke, reduce severity of acute chest syndrome, and other vasoocclusive complications. Finally, HBOCs have the potential to alter the pathogenesis of SCD.

Feasibility and challenges of addressing this CQ or CC:

The problems in managing chronic RBC transfusion in SCD remain the same as they have been for decades: all immunization, iron overload, and infection transmission. It is clear that traditional serological RBC phenotyping is unable to detect several variants of RBC antigens, especially those in the Rh system, in populations of African descent. This leads to erroneous phenotyping and the appearance of “auto antibodies” that are truly alloantibodies resulting from transfusion of mismatched blood. As a result, people with SCD are the most frequent users of the American Rare Donor Program.

Name of idea submitter and other team members who worked on this idea:
Kwaku Ohene-Frempong, MD

Can new advances in allogeneic blood or marrow transplantation (BMT) make the procedure a safe and universally available therapeutic strategy for treating non-malignant blood and immune disorders such as sickle cell anemia, thalassemia, aplastic anemia, and severe combined immune deficiency?

The ability of allogeneic blood or marrow transplantation (BMT) to cure diverse non-malignant diseases is well-documented. However, widespread use in diseases such as sickle cell anemia that cause substantial morbidity and shorten life but are not immediately life-threatening, has been limited by transplant-related toxicity and mortality especially in the majority of these patients who lack HLA-matched donors. Several new therapeutic approaches now exist that are promising strategies, separately or in combination, for addressing issues of donor availability, graft rejection, organ toxicity and acute and chronic graft-versus-host disease more effectively. Evaluation and refinement of these therapeutic strategies in both preclinical and Phase I-III clinical trials now offers a real possibility that allogeneic BMT could be applied early in the course of these diseases, allowing normal growth, development, quality of life and lifespan. If successful, allogeneic BMT offers a major advantage over gene therapy approaches even if such approaches become possible in the future; i.e., allogeneic BMT can be done with low-dose, non-toxic conditioning while gene therapy requires high-dose myeloablative therapy which not only can be toxic/fatal to these patients who often have end-organ dysfunction but also universally induces infertility, a major concern of patient groups who usually survive beyond child-bearing years.

Feasibility and challenges of addressing this CQ or CC:

There are now single institution and registry (CIBMTR) data showing that related haploidentical allogeneic BMT using post-transplantation cyclophosphamide (PTCy) produces results similar to those seen with HLA-matched sibling donors. Accordingly, every patient in need of allogeneic BMT now can safely undergo the procedure, including those ethnic groups (such as African-Americans and Hispanics) who are unlikely to find a donor in unrelated registries. Combining PTCy with other approaches for preventing graft-versus-host disease (GVHD) can even eliminate GVHD and transplant-related mortality. Although recurrence of malignant diseases remains an issue, especially as GVHD is eliminated, relapse is not a concern for non-malignant diseases after successful allogeneic engraftment. Moreover, the average cost of allogeneic BMT, about $150K, is a cost-savings over the long-term management of many of these diseases. The NHLBI-funded BMT Clinical Trials Network (CTN) has developed the infrastructure to rapidly and efficiently carry out large multi-institutional BMT trials. Over the last 15 year, thousands of patients have been entered on BMT CTN trials. Of note, African-Americans and Hispanics remarkably represent 30% of the accruals on one such trial, CTN1101, studying unrelated umbilical cord and related haploidentical allogeneic BMT. However, funding for the infrastructure for continuing this work remains problematic, since BMT trials generally lack corporate funding.

Name of idea submitter and other team members who worked on this idea:
Rick Jones

Voting

Sickle cell disease is now understood as a disease of inflammation in addition to abnormal red blood cells. It is likely persons with sickle cell trait are also negatively affected by the damage caused by inflammation. There is a significant racial disparity in hypertension, stroke, and chronic kidney disease. It remains unclear the degree to which sickle cell trait contributes to this disparity. It also remains unclear
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Recent evidence in the United States emphasizes the possible health risks for individuals with HbAS including increased incidence

of renal failure and malignancy, thromboembolic disorders, splenic infarction as a high altitude complication, and exercise-related sudden death. Additional concerns include the increase risk of hypertension from endothelial scaring and additional vascular abnormalities. Early preventative therapies for persons with HbAS (sickle cell trait) could reduce the progression of cardiovascular disease in manny individuals if found to be of concern.

Feasibility and challenges of addressing this CQ or CC:

1. Several identified impediments to research of sickle cell trait have included under-representation of the African– American community in preclinical and translational research projects and limited study in health disparities research (Am J Hematol . 2012 March ; 87(3): 340–346).

3. The diagnosis of the carrier state for a genetic disease may be associated with serious health problems that can lead to widespread bioethical and social stigmatization and additional concerns including the increased need for testing and counseling

Name of idea submitter and other team members who worked on this idea:
Julie Kanter

1) SCD is a hypercoagulable state; patients are at increased risk for VTE compared with African American controls.

2) Abnormalities in the coagulation system exist in SCD patients

3) Increased platelet activation occurs in SCD patients with an elevated TRV, but it is not clear if patients with an elevated TRV or PH have an increased incidence of VTE.

4) Increased risk of ischemic strokes in this population supports the notion that thrombosis is a disease modulator

5) Autopsy specimens of the lungs from SCD patients reveal a thrombotic arteriopathy.

6) Acute pulmonary embolism can be a trigger of the acute chest syndrome (ACS).

7) In addition to ischemic risks, SCD patients are at increased risk for hemorrhage particularly of the cerebral and retinal vasculature.

Feasibility and challenges of addressing this CQ or CC:

Areas of controversy:

1) What is the diagnostic modality of choice for acute and chronic VTE in the SCD population? V/Q scans are notoriously abnormal and often difficult to interpret, and there is a historic (but not clinically substantiated) fear of CT/A grams in these patients due to a fear that IV contrast will promote sickling.

2) Does VTE occur in ACS or are these all bone marrow/fat emboli?

3) What role do platelets play in the endothelial dysfunction of SCD?

4) What is the appropriate length of time for anti-coagulation after a first VTE?

5) What are indications for lifelong anti-coagulation in SCD patients?

6) What is the role of VTE in SCD patients with PH? Do these patients have an increased prevalence of VTE and are there outcome benefits for anti-coagulation in those with and without a history of VTE?

Name of idea submitter and other team members who worked on this idea:
ATS Member

Unless an individual is a candidate for transplantation, sickle cell will be a lifelong challenge. Much effort has been focused in the pediatric area and on physical aspects of the disease. However, adult care and mental/psycho-social health have not been adequately addressed. A holistic approach across the lifespan would fill these gaps and perhaps lead to better health outcomes and addresses NHLBI's goal of reducing the burden of human disease.

Name of idea submitter and other team members who worked on this idea:
Sickle Cell Warriors, Inc. community members

To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.